Multiple sclerosis and amyotrophic lateral sclerosis: is there an association or a red flag? A case report and literature review

Background Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that causes damage to the myelin and axons and is caused by genetic or environmental factors. Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive degeneration of the motor neurons resulting in the presence of upper and lower motor-neuron signs and symptoms. Case presentation A 46-year-old female patient presented with symmetrical weakness of the lower limbs and numbness that developed over weeks. Magnetic resonance imaging (MRI) of the brain exhibited typical demyelination features, high signal abnormality involving the periventricular and subcortical white matter, and an oval-shaped lesion. The patient was diagnosed with MS based on the clinical presentation and radiological examination. However, there was rapid progression of the symptoms, involvement of bulbar dysfunction, and muscle atrophy. Furthermore, the patient did not respond to acute therapy and immunotherapy, which made the diagnosis of MS less likely or suggested that it could be associated with another diagnosis. Her neurophysiological test met the criteria of ALS, and she was started on riluzole. Literature review We reviewed all articles from 1986 to 2023, and there were 32 reported cases describing the co-occurrence of ALS and MS in different populations. Our case is the 33rd, and to our knowledge, it is the only case reported in the Middle East and specifically in Saudi Arabia. The main proposed mechanism according to postmortem examinations is a combination of degenerative and inflammatory processes with a cascade of production of reactive oxygen species and nitric oxide, which lead to cell death and apoptosis during concomitant ALS with MS. Conclusion The co-occurrence of ALS and MS is extremely rare, but it can be explained by pathogenesis related to neurodegeneration, inflammation, or genetic susceptibility. Rapid progressive motor and bulbar symptoms could be red-flag symptoms, extensive evaluation might be needed for these patients.


Background
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that causes damage to myelin and axons, influenced by genetic and environmental factors.The autoimmune process in MS leads to the degeneration of myelin sheaths.Common presenting symptoms include sensory, motor, and vision issues, as well as imbalance [1,2].Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the brain and spinal cord, characterized by the presence of upper and lower motor neuron signs and symptoms [3].ALS impacts bulbar, cervical, lumbosacral, and thoracic motor neurons [4].
Both MS and ALS can exhibit non-motor symptoms.Neuropsychiatric symptoms in ALS most commonly include depression and anxiety, while cognitive impairment may arise due to frontal lobe dysfunction.Executive dysfunction is frequently reported in ALS [5].In contrast, cognitive issues in MS can result from cortical lesions that lead to gray matter atrophy, causing a variety of cognitive symptoms.Other non-motor symptoms in both conditions include fatigue, pain, pseudobulbar affect, sialorrhea, and autonomic dysfunction [4].Notably, autonomic dysfunction in ALS is an independent factor contributing to disease progression and is associated with more rapid rates of motor functional decline and shorter survival [6].
The co-occurrence of MS and ALS is rare; however, the proposed link involves genetic factors and demyelination activity affecting axon cells alongside the degeneration of anterior horn cells, leading to programmed cell death [3].Activation of neuroinflammation and neurodegenerative processes due to environmental or genetic factors may explain the connection between these two diseases [7,8].A notable case of co-occurrence involved a patient with ALS who exhibited features of MS, potentially driven by a hexanucleotide repeat expansion of C9ORF72 [1].This case highlighted a challenging presentation of progressive bulbar symptoms, raising questions about whether the patient was experiencing a progressive form of MS or concomitant diseases.
We report on a middle-aged woman diagnosed with MS who was later found to have ALS, along with an overview of 32 additional cases and a description of the link between these two diseases.

Case presentation
The patient was a 46-year-old woman with a known case of type 2 diabetes mellitus.In April 2022, the patient started to have progressive symmetrical weakness of the lower limbs and numbness, which developed over weeks and was progressive in nature.She also started to have difficulty with walking and eventually required a wheelchair.She denied having any history of recent travel, rawmilk ingestion, vaccination, family history of the same presentation, illicit drug use, fever, or upper-respiratorytract infection.She also denied having any gastrointestinal or genitourinary symptoms.
The patient was admitted to another facility, and the investigations performed included lumbar puncture and magnetic resonance imaging (MRI) of the brain.The MRI showed non-specific white-matter lesions, and the patient was diagnosed with demyelinating disease.She received pulse steroid therapy and was discharged, but there was minimal improvement regarding her muscle weakness after she went home.
In September 2022, her weakness progressed further with upper limb weakness, and she also developed difficulty in breathing and swallowing, along with worsening of her muscle weakness.Eventually, she was tracheostomized.During her admission to the other facility, she again received pulse steroid therapy, intravenous immunoglobulin, and one dose of ocrelizumab due to an impression of secondary progressive MS.Because she was not showing any improvement in functional status, she was eventually referred to our institution for further investigations and management (Fig. 1).

Clinical findings
The patient was on a mechanical ventilator with a trachea tube, nasogastric tube, and indwelling Foley catheter.She was awake, alert, and responding to commands.The results of cranial nerve examination were normal except for atrophy and fasciculation of the tongue with an exaggerated jaw reflex.Motor examination revealed atrophied thenar muscles, hypertonia of the upper limbs, and hypotonic lower limbs.
The Medical Research Council (MRC) grade of limb power for the upper limbs was + 2 for proximal muscles and + 3 distally at the level of the wrist and fingers.For the lower limbs, the MRC was + 2 proximally and + 1 distally at the level of the ankle, feet, and toes.The score for deep tendon reflexes was + 2 for the upper limbs with spreading reflexes, and the lower limbs were areflexic with mute plantar reflex, no clonus, and negative Hoffman sign.Sensory examination revealed decreased pinprick sensation and an absence of proprioception in the lower limb, and no sensory level was detected.The cerebellar examination was limited because of severe weakness.

Laboratory findings
The patient's vitamin levels were all within normal limits, including vitamin B12 and its metabolites methylmalonic acid and homocysteine.The results of a thyroid function test including thyroid antibodies were normal.Her cerebrospinal fluid (CSF) showed a normal cell count, normal levels of glucose, protein, and lactate, negative culture results, and an oligoclonal band.Moreover, the results of serological and CSF tests for Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Haemophilus influenzae infection were negative.Autoimmunological diagnostic including antinuclear antibody (ANA), complement fixing ANA (C-ANA), and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) were negative, as were tests for coeliac disease (antigliadin antibodies and antitransglutaminase antibodies).Moreover, paraneoplastic antibodies were sent through the serum and CSF, and the result was negative.

Radiological features
Brain and spine MRI showed evidence of scattered foci of hyperintense T2/FLAIR signal abnormality involving the periventricular and subcortical white matter in both cerebral hemispheres with limited involvement of the corpus callosum.Some of these lesions appeared perpendicular to the lateral surface of the lateral ventricle and suggested a demyelinating process.There was no pathological enhancement suggesting active disease.Imaging of the cord demonstrated normal alignment of the vertebral bodies.We performed 18-fluoro-2-deoxyglucose (FDG) whole-body positron emission tomography, which showed no detectable metabolically active lesions that could suggest malignancy in the rest of the scanned body.The MRI did not show the reason for rapid progression, and a diagnosis of MS was made based on radiological features (Fig. 2).

Electrophysiological diagnosis
Due to the presence of both upper and lower motor signs in examination, a nerve conduction study (NCS) and electromyography (EMG) were done.The motor NCS revealed that the right median to abductor pollicis brevis was absent, the right ulnar to abductor digiti minimi showed a very small compound motor action potential of 0.4 mV, the right tibial to adductor hallucis was absent, and so was the right peroneal to extensor digitorum brevis.The sensory NCS results were normal.
In EMG, three segments were sampled.In the bulbar segment, the right tongue showed features of active Fig. 2 Axial and sagittal view of brain MRI showing scattered foci of hyperintense T2/FLAIR signal abnormality involving the periventricular and subcortical white matter in both cerebral hemispheres.Some of these lesions appeared perpendicular to the lateral surface of the lateral ventricle and suggested a demyelinating process denervation (+ positive sharp waves and + fibrillations).The cervical segment (right deltoid, extensor digitorum communis, and biceps) showed features of active denervation (+ positive sharp waves and + fibrillations).The lumbar segment (right tibialis anterior and vastus medialis) showed features of active denervation (+ positive sharp waves and + fibrillations).These findings are compatible with widespread motor neuron disease (Fig. 3).

Discussion
The patient was diagnosed with MS and was managed based on the radiological features and clinical assessment.The rapid progression of the symptoms,  The combination of MS and ALS is rare but can be explained by links between neurodegeneration, inflammation, and genetic susceptibility.In post-mortem pathological findings, demyelinating activity is observed, and degenerative processes of the anterior horn cells occur at multiple serial lumbosacral cord levels through an inflammatory cascade.This leads to the release of reactive oxygen species and nitric oxide, cell death, and apoptosis, which are observed concomitantly in ALS with MS [3][4][5][6][7].In a case series study by Ismail et al., the co-occurrence of MS in a patient with ALS was explained as being driven in some way by a hexanucleotide repeat expansion of C9ORF72.The study highlighted that more than 1% of patients with ALS may have a history of MS [8].Fiondella et al. reported one case of heterozygous mutation in FUS exon 15 [1].
So far, there have been 32 reported cases of the cooccurrence of ALS and MS in different populations, which have mainly occurred in Europe and North America.Our case is the 33rd to be reported and is the only case to our knowledge that has occurred in the Middle East and specifically in Saudi Arabia.We reviewed all related articles from 1986 to 2023.Most of the cases were females (25 out of 33), and 8 were males.The mean age of the onset of ALS is 52 years with a range of 34 to 72 years.The mean age of the onset of MS is 41 years.In some studies, no autopsies or genetic tests were performed, but In the different cases, patients were diagnosed with MS initially and were later diagnosed with late-onset or rapid-onset ALS.Autopsy has shown a loss of myelinated axons and neuronal loss with gliosis of the motor neuron cells [8].Only 5 patients have been reported to be positive for C9orf72 out of the 33 cases reviewed, but genetic tests were not done in all cases.HLA genotyping performed on genomic DNA has also been studied, and three cases showed positivity for HLA-B*18:01A according to Dattola et al.This antigen could play an important role in activating both neuroinflammation and neurodegenerative processes [9].Table 1 shows the characteristics and diagnostic information of the 33 cases (Figs. 4  and 5).

Conclusion
The co-occurrence of ALS and MS is extremely rare, but it can be explained by a mix of pathogenesis involving neurodegeneration, inflammation, and genetic susceptibility.Careful evaluation is needed for patients with rapid progressive motor and bulbar symptoms who are initially diagnosed with MS as this presentation could be a red flag.Extensive evaluation might be needed for these patients.To gain more understanding of the co-occurrence, pathological testing, genetic testing, and HLA genotyping should be considered for diagnosis.

Fig. 3
Fig. 3 Nerve conduction study showing A very low compound motor action potential (CMAP) of right ulnar nerve responses, B absent CMAP of the left fibular nerve responses, and C, D normal sensory nerve action potential (SNAP) of upper and lower-limb sensory nerve stimulation sampled from the sural and median nerve.O: onset of the wave.P: peak of the wave.T: terminal part of the wave

Fig. 4 Fig. 5
Fig. 4 Illustration of the main characteristics of the 33 cases of MS with ALS from 1986 to 2023.There is a predominance of females (25 cases).The onset of MS occurs at an average age of 41 years, with late-onset ALS diagnosis occurring at the age of 52 years.C9orf72 was found in only 5 cases

Table 1
Demographic, clinical, and neurogenetic features of patients with co-occurring MS/ALS diagnoses

Table 1 (
continued) Portugalinvolvement of bulbar dysfunction, and lack of response to acute therapy and immunotherapy made the diagnosis of MS less likely or suggested an association with another diagnosis.Clinical features and the results of the neurophysiological investigation met the El Escorial criteria for ALS.She was started on riluzole at 50 mg twice per day and was referred for multidisciplinary care.